Combination of triazine derivatives and insulin sensitisers

ABSTRACT

The present invention relates to combinations of triazine derivatives and of insulin sensitisers.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition oftriazine derivatives or described pharmaceutically acceptable saltsthereof with an insulin sensitiser, for the manufacture of a medicamentthat can be used in the treatment of non-insulin-dependent diabetes andpathologies associated with insulin resistance syndrome.

TECHNICAL BACKGROUND

“Diabetes mellitus” (or diabetes) is one of the most prevalent diseasesin the world today. Individuals suffering from diabetes have beendivided into two classes, namely type I or insulin-dependent diabetesmellitus and type II or non-insulin-dependent diabetes mellitus (NIDDM).Non-insulin-dependent diabetes mellitus (NIDDM) accounts forapproximately 90% of all diabetics, and is estimated to affect 12 to 14million adults in the United States alone (6.6% of the population).NIDDM is characterised both by fasting hyperglycaemia and exaggeratedpostprandial increases in plasmatic glucose levels. NIDDM is associatedwith a variety of long-term complications, including microvasculardiseases, such as retinopathy, nephropathy and neuropathy, andmacrovascular diseases, such as coronary heart disease. Numerous studiesin animal models show a causal relationship between long-termcomplications and hyperglycaemia. Recent results obtained by theDiabetes Control and Complications Trial (DCCT) and the StockholmProspective Study have for the first time demonstrated this relationshipin man by showing that insulin-dependent diabetics have a substantiallylower risk of development and progression of these complications if theyare subjected to tighter glycaemic control. Tighter control is alsoexpected to benefit NIDDM patients.

Hyperglycaemia in the case of NIDDM is associated with two biochemicalanomalies, namely insulin resistance and insufficiency of insulinsecretion.

The initial treatment of NIDDM is based on a controlled diet andcontrolled physical exercise, since a considerable number of diabeticsare over weight or obese (˜67%) and since loss of weight can improveinsulin secretion and sensitivity to insulin and lead to normalglycaemia.

Patients suffering from a hyperglycaemia that cannot be controlledsolely by a diet and/or physical exercise are then treated with oralantidiabetics.

A number of categories of oral antidiabetics are currently used inmonotherapy for the treatment of NIDDM:

-   -   insulin secretion stimulators. They are represented, firstly, by        sulfonylureas (SU) and by “glinides”. As regards SUs, mention        will be made in particular of carbutamide (Glucidoral®),        glibenclamide/glyburide (Daonil®, Euglucan®), glibomuride        (Glutril®), gliclazide (Diamicron®), glimepiride (Amarel®) and        glipizide (Glibenese®). As regards the “glinides”, mention will        be made in particular of repaglinide (NovoNorm®);    -   agents that reduce glucogenesis, represented by the biguanides.        Mention will be made in particular of metformin (Glucophage®,        Stagid®);    -   insulin sensitisers, represented mainly by thiazolidinediones        (TZD). Mention will be made in particular of pioglitazone        (Actos®) and rosiglitazone (Avandia®);    -   alpha-glucosidase inhibitors. Mention will be made in particular        of acarbose (Glucor®) and miglitol (Diastabol®).

However, the monotherapy may show a loss of efficacy over time. This isreferred to as “secondary deficiency”. This may represent up to 50%unsatisfactory response after 10 years of treatment. The studiesconducted have shown that it is possible to deal with this problem bycombining in the same pharmaceutical form metformin with TZDs (EP 869796 B1 or EP 861 666 B1).

Moreover, the combination metformin+rosiglitazone (Avandamet®) has beenmarketed.

However, these metformin-based combinations have adverse effectsassociated with the use of metformin, in particular intestinal symptoms,such as nausea, diarrhoea and abdominal pain. Triazine derivatives withan antidiabetic effect comparable to metformin have been described in WO01/55122. However, their combination has never been suggested.

The applicant has developed a novel pharmaceutical compositioncomprising an antidiabetic agent of triazine type, such as thosedescribed in WO 01/55122 and an insulin sensitiser.

Unexpectedly, the combinations according to the invention showsynergistic activity and significantly reduce the side effects of theknown combinations.

DESCRIPTION OF THE INVENTION

The present invention relates to a novel pharmaceutical composition tocomprising an insulin sensitiser and a compound of the general formula(I):

in which:R1, R2, R3 and R4 are independently chosen from the following groups:

-   -   H,    -   (C1-C20)alkyl optionally substituted by halogen, (C1-C5)alkyl,        (C1-C5)-alkoxy or (C3-C8)cycloalkyl,    -   (C2-C20)alkenyl optionally substituted by halogen, (C1-C5)alkyl        or (C1-C5)alkoxy    -   (C2-C20)alkynyl optionally substituted by halogen, (C1-C5)alkyl        or (C1-C5)alkoxy    -   (C3-C8)cycloalkyl optionally substituted by (C1-C5)alkyl or        (C1-C5)-alkoxy    -   hetero(C3-C8)cycloalkyl bearing one or more heteroatoms chosen        from N, O and S and optionally substituted by (C1-C5)alkyl or        (C1-C5)alkoxy    -   (C6-C14)aryl(C1-C20)alkyl optionally substituted by amino,        hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,        (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,        (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,        carboxymethyl or carboxyethyl,    -   (C6-C14)aryl optionally substituted by amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C1-C13)heteroaryl bearing one or more heteroatoms chosen from        N, O and S and optionally substituted by amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

to R1 and R2, on the one hand, and R3 and R4, on the other hand,possibly forming with the nitrogen atom an n-membered ring (n between 3and 8) optionally containing one or more heteroatoms chosen from N, Oand S and possibly being substituted by one or more of the followinggroups: amino, hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,(C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl,

R5 and R6 are independently chosen from the following groups:

-   -   H,    -   (C1-C20)alkyl optionally substituted by amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C2-C20)alkenyl optionally substituted by amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C2-C20)alkynyl optionally substituted by amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)-aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C3-C8)cycloalkyl optionally substituted by amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   hetero(C3-C8)cycloalkyl bearing one or more heteroatoms chosen        from N, O and S and optionally substituted by amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C6-C14)aryl optionally substituted by amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C1-C13)heteroaryl bearing one or more heteroatoms chosen from        N, O and S and optionally substituted by amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,    -   (C6-C14)aryl(C1-C5)alkyl optionally substituted by amino,        hydroxyl, thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy,        (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,        (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,        carboxymethyl or carboxyethyl,    -   R5 and R6 possibly forming with the carbon atom to which they        are attached an m-membered ring (m between 3 and 8) optionally        containing one or more heteroatoms chosen from N, O and S and        possibly being substituted by amino, hydroxyl, thio, halogen,        (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,        or possibly forming with the carbon atom a C10-C30 polycyclic        residue optionally substituted by amino, hydroxyl, thio,        halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,        R5 and R6 together also possibly representing the group ═O or        ═S, the nitrogen atom of a heterocycloalkyl or heteroaryl group        possibly being substituted by a (C1-C5)alkyl, (C3-C8)cycloalkyl,        (C6-C14)aryl, (C6-C14)aryl(C1-C5)alkyl or (C1-C6)acyl group,        and also the racemic forms, tautomers, enantiomers,        diastereoisomers, epimers and mixtures thereof, and the        pharmaceutically acceptable salts.

One particular group of the invention concerns the pharmaceuticalcompositions according to the invention in which the triazinederivatives are compounds of the formula (I) in which R5 is hydrogen.

Another particular group of the invention concerns the pharmaceuticalcompositions according to the invention in which the triazinederivatives are to compounds of the formula (I) in which R5 and R6 formwith the carbon atom to which they are attached an m-membered ring (mbetween 3 and 8) optionally containing one or more heteroatoms chosenfrom N, O and S and possibly being substituted by one or more of thefollowing groups: (C1-C5)alkyl, amino, hydroxyl, (C1-C5)alkylamino,alkoxy(C1-C5), (C1-C5)alkylthio, (C6-C14)aryl,(C6-C14)aryl(C1-C5)alkoxy,

or form with the carbon atom a C10-C30 polycyclic residue optionallysubstituted by amino, hydroxyl, thio, halogen, (C1-C5)alkyl,(C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, (C6-C14)aryloxy,(C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl, carboxyl,carboxymethyl or carboxyethyl.

Another particular group of the invention concerns the pharmaceuticalcompositions according to the invention in which the triazinederivatives are compounds of the formula (I) in which R5 and R6 areindependently chosen from the following groups:

-   -   (C1-C20)alkyl groups optionally substituted by amino, hydroxyl,        thio, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,        (C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy,        cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl.

Preferably, R1, R2, R3 and R4 are independently chosen from H and(C1-C20)alkyl groups optionally substituted by halogen, (C1-C5)alkyl,(C1-C5)alkoxy or (C3-C8)cycloalkyl; more preferably, R1=R2=H andR3=R4=(C1-C20)alkyl optionally substituted by halogen, (C1-C5)alkyl,(C1-C5)alkoxy, (C3-C8)cycloalkyl or vice versa.

Preferably, R5 and R6 are independently chosen from H and (C1-C20)alkylgroups optionally substituted by amino, hydroxyl, thio, halogen,(C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino,(C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano, trifluoromethyl,carboxyl, carboxymethyl or carboxyethyl; more preferably, R5=H andR6=(C1-C20)alkyl optionally substituted by amino, hydroxyl, thio,halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,(C1-C5)alkylamino, (C6-C14)aryloxy, (C6-C14)aryl(C1-C5)alkoxy, cyano,trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl or vice versa.

A more particular group of the invention concerns the pharmaceuticalcompositions according to the invention in which the triazinederivatives are compounds of the formula (I) in which R1 and R2 are amethyl group and R3 and R4 represent a hydrogen.

The term “m-membered ring formed by R5 and R6” in particular means asaturated ring, such as a cyclohexyl, piperidyl or tetrahydropyranylgroup.

The term “polycyclic group formed by R5 and R6” means an optionallysubstituted carbon-based polycyclic group and in particular a steroidresidue.

Compounds of the formula (I) that may especially be mentioned include:

Formula Salt  1

HCl  2

HCl  3

 4

HCl  5

Methane- sulfonate  6

 7

HCl  8

HCl  9

HCl 10

HCl 11

HCl 12

HCl 13

14

Fumarate 15

HCl 16

HCl 17

HCl 18

HCl 19

HCl 20

Carbonate 21

Carbonate 22

HCl 23

HCl 24

HCl 25

HCl 26

HCl 27

HCl 28

HCl 29

Carbonate 30

Carbonate 31

HCl 32

Carbonate 33

HCl 34

para- Toluene- sulfonate 35

HCl 36

para- Toluene- sulfonate 37

para- Toluene- sulfonate 38

HCl 39

HCl 40

HCl 41

para- Toluene- sulfonate 42

HCl 43

HCl 44

HCl 45

para- Toluene- sulfonate

and more preferably the compound of Example 18.

According to yet another preferred embodiment, the invention moreparticularly relates to pharmaceutical compositions chosen from:

-   -   (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine        hydrochloride, and rosiglitazone;    -   (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine        hydrochloride, and troglitazone;    -   (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine        to hydrochloride, and pioglitazone;    -   (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine        hydrochloride, and muraglitazar.

The term “insulin sensitiser” means any compound capable of increasingthe sensitivity of tissues to insulin. Insulin sensitisers include, forexample, tyrosine phosphatase inhibitors (PTP inhibitors), GSK-3inhibitors, retinoid X receptor agonists (RXR agonists), glitazones(TZD), non-TZD PPAR_(γ) agonists, PPAR_(α)/PPAR_(γ) double agonists,agonists based on compounds containing vanadium, and biguanides, forinstance metformin. Insulin sensitisers may also be in the form ofpharmaceutically acceptable salts, such as, in a non-limiting manner,the hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate,phosphate, citrate, methanesulfonate, trifluoroacetate or acetate, thesodium ion, the potassium ion, the calcium ion or the magnesium ion.

The term “glitazones” includes, in a non-limiting manner, englitazone,darglitazone, ciglitazone, DRF2189, BM-13.1246, AY-31637, YM268,AD-5075, DN-108, rosiglitazone, pioglitazone, troglitazone, MCC555,T-174 and KRP297.

The term “non-TZD PPAR_(γ) agonist” more particularly includesN-(2-benzoylphenyl)-L-tyrosine analogues, such as, in a non-limitingmanner, GI-262570 and JTT501.

The term “PPAR_(α)/PPAR_(γ) double agonist” includes, in a non-limitingmanner, compounds, such as: NNC-61-4655, TZD18, LY-510929, LY-465608,LSN862, GW-409544, Muraglitazar, Ragaglitazar, Tesaglitazar, to and alsothe compounds described in WO 03/011819 (Example 8) and WO 00/039113(Example 16b describing oxeglitazar).

The compounds of the invention of the formula (I) as defined above,containing a sufficiently basic function, or both, may include thecorresponding pharmaceutically acceptable salts of organic or mineralacids.

For the purposes of the present invention, the term “correspondingpharmaceutically acceptable salts of organic or mineral acids” means anysalt prepared from any non-toxic pharmaceutically acceptable organic orinorganic acid. Such acids include acetic acid, benzenesulfonic acid,benzoic acid, citric acid, carbonic acid, ethanesulfonic acid, fumaricacid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid,lactic acid, mandelic acid, malic acid, maleic acid, methanesulfonicacid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoricacid, succinic acid, tartaric acid and para-toluenesulfonic acid.Hydrochloric acid is advantageously used.

The invention also relates to the chiral salts of the compounds of theformula (I) used for the separation of the racemates of the compounds ofthe formula (I).

By way of example, the following chiral acids are used:(+)-D-di-O-benzoyltartaric acid, (−)-L-di-O-benzoyltartaric acid,(−)-L-di-O,O′-p-toluoyl-L-tartaric acid,(+)-D-di-O,O′-p-toluoyl-L-tartaric acid, (R)-(+)-malic acid,(S)-(−)-malic acid, (+)-camphanic acid, (−)-camphanic acid,R-(−)-1,1′-binaphthalen-2,2′-diylhydrogenophosphonic acid, (+)-camphoricacid, (−)-camphoric acid, (S)-(+)-2-phenylpropionic acid,(R)-(+)-2-phenylpropionic acid, D-(−)-mandelic acid, L-(+)-mandelicacid, D-tartaric acid, L-tartaric acid, or a mixture of two or morethereof.

The compounds of the formula (I) above also include the prodrugs ofthese compounds.

The term “prodrugs” means compounds which, when administered to thepatient, are chemically and/or biologically converted in the live bodyinto compounds of the formula (I).

In the present description, the terms used have, unless otherwiseindicated, the following meanings:

-   -   the term “(C1-C20)alkyl” denotes a linear or branched alkyl        radical containing from 1 to 20 carbon atoms. Among the C1-C20        alkyl radicals that may especially be mentioned, in a        non-limiting manner, are methyl, ethyl, propyl, isopropyl,        butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl,        dodecyl, hexadecyl and octadecyl radicals;    -   the term “(C1-C20)alkenyl” denotes a linear or branched        hydrocarbon-based radical containing one or more unsaturations        in double bond form. As alkylene radicals containing from 1 to        20 carbon atoms, mention may be made, in a non-limiting manner,        of ethenyl, prop-2-enyl, but-2-enyl, but-3-enyl, pent-2-enyl,        pent-3-enyl and pent-4-enyl radicals;    -   the term “(C1-C20)alkynyl” denotes a linear or branched        hydrocarbon-based radical containing one or more unsaturations        in triple bond form. As alkylene radicals containing from 1 to        20 carbon atoms, mention may be made, in a non-limiting manner,        of ethynyl, prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl,        pent-3-ynyl and pent-4-ynyl radicals;    -   the term “alkoxy” refers to the term “alkyl-oxy”;    -   the term “halogen” refers, in a non-limiting manner, to        fluorine, chlorine or bromine;

the term “(C6-C14)aryl(C1-C20)alkyl” refers to the corresponding-alkylaryl groups. Mention will be made in particular of benzyl andphenethyl groups;

the term “(C6-C14)aryl” refers to an aromatic group containing from 6 to14 carbon atoms with at least one of the rings having a system ofconjugated pi electrons, and including biaryls, which may be optionallysubstituted. Mention will be made in particular of biphenyl, phenyl,naphthyl, anthryl and phenanthryl radicals;

-   -   the term “hetero(C6-C14)aryl” refers to a 6-14-membered aromatic        heterocycle containing 1-4 heteroatoms, the other atoms being        carbon atoms. Among the heteroatoms, mention will be made in        particular of oxygen, sulfur and nitrogen. Among the heteroaryl        radicals, mention will be made more particularly of furyl,        thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, oxazolyl,        oxadiazolyl, isoxazolyl, quinolyl and thiazolyl radicals;    -   the term “(C3-C8)cycloalkyl” refers to a saturated        hydrocarbon-based ring and containins monocyclic, bicyclic and        polycyclic radicals containing from 3 to 8 carbon atoms. Mention        will be made, in a non-limiting manner, of cyclopropyl and        cyclobutyl radicals.

It will be appreciated that the compounds that are useful according tothe present invention may contain asymmetric centres. These asymmetriccentres may be, independently, in R or S configuration. It will be clearto a person skilled in the art that certain compounds that are usefulaccording to the invention may also exhibit geometrical isomerism. Itshould be understood that the present invention includes individualgeometrical isomers and stereoisomers and mixtures thereof, includingracemic mixtures, of compounds of the formula (I) above. Isomers of thistype can be separated from mixtures thereof by application or adaptationof known processes, for example chromatography techniques orrecrystallisation techniques, or they are prepared separately fromsuitable isomers of their intermediates.

The enantiomers of the compounds according to the invention and theprocess for the preparation of them are especially described in patentapplication WO 2004/089917, the content of which is incorporated hereinby reference.

The present patent application also concerns the polymorphic forms ofthe compounds, as obtained according to patent application WO2004/089917, for instance the A1 polymorphic form of the salt(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazinehydrochloride.

The present invention also relates to the other polymorphic forms of thecompounds, such as the H1 polymorphic form of the salt(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazinehydrochloride, which can be prepared as follows:

Approximately 3 g of the A1 form of Example 18 are dissolved in 50 ml of1 mol/l HCl at room temperature. The clear solution obtained is left toevaporate at room temperature, in an open beaker, until a solid residuecrystallises.

The characterisation is performed by:

FT-IR spectroscopy:

-   -   Brüker Vector 22    -   2 cm⁻¹ spectral resolution    -   32 scans    -   KBR discs (analogous to method A AA21505)    -   To evaluate the intensity of the IR bands, the IR spectra were        normalised by vectorisation in the spectral range 4000-400 cm⁻¹        as an absorption spectrum.

Preadjustment was performed:

-   -   s: A>0.05    -   m: 0.01<A<0.05    -   w: A<0.01.

FT-Raman spectroscopy:

Brüker RFS-100

-   -   excitation: 1064 nm    -   spectral resolution: 1 cm⁻¹    -   1000 mW    -   1000 scans    -   focalised    -   aluminium crucible (analogous to method RA AA21505)    -   To evaluate the intensity of the Raman bands, Raman spectra were        normalised by vectorisation in the spectral range 3600-200 cm⁻¹.        Preadjustment was performed:        -   s: A>0.05        -   m: 0.01<A<0.05        -   w: A<0.01

Powder x-ray diffraction (XRD)

-   -   diffractometer D5000 (Brüker AXS)    -   radiation CuKα1 at 1.5406 Å (U=30 kV, A=40 mA)    -   Transmission mode    -   Detector in sensitive position    -   Primary monochromator    -   Angle range: 3-65 °2θ    -   Stage width: 0.05 °2θ    -   Measuring time/stage: 1.4 s    -   The XRD machine is set at 2θ±0.1°.

Results

A1 form:

XRD:

No. d[Å] 2θ l/lo 1 5.98 14.8 85 2 5.26 16.8 83 3 4.35 20.4 30 4 3.5724.9 100 5 3.50 25.4 53 6 3.36 26.5 96 7 3.31 26.9 52 8 3.04 29.3 57 92.90 30.8 30 10 2.74 32.7 35FT-IR bands (in cm⁻¹):3384+/−1.5 (m), 3199+/−1.5 (m), 3163+/−1.5 (m), 3107+/−1.5 (m),2993+/−1.5 (m), 2983+/−1.5 (m), 1652+/−1.5 (s), 1606+/−1.5 (s),1576+/−1.5 (s), 1557+/−1.5 (s), 1505+/−1.5 (s), 1449+/−1.5 (m),1427+/−1.5 (m), 1405+/−1.5 (m), 1383+/−1.5 (m), 1348+/−1.5 (m),1306+/−1.5 (m), 1263+/−1.5 (w), 1235+/−1.5 (w), 1185+/−1.5 (w),1096+/−1.5 (w), 1068+/−1.5 (w), 980+/−1.5 (w), 946+/−1.5 (w), 868+/−1.5(w), 761+/−1.5 (w), 687+/−1.5 (m), 655+/−1.5 (m), 558+/−1.5 (w),521+/−1.5 (w), 478+/−1.5 (w)FT-Raman bands (in cm⁻¹):3217+/−1.5 (w), 2994+/−1.5 (m), 2983+/−1.5 (m), 2936+/−1.5 (s),2883+/−1.5 (m), 1645+/−1.5 (w), 1602+/−1.5 (m), 1554+/−1.5 (m),1453+/−1.5 (m), 1428+/−1.5 (m), 1349+/−1.5 (w), 1308+/−1.5 (w),979+/−1.5 (m), 866+/−1.5 (w), 761+/−1.5 (w), 686+/−1.5 (s), 583+/−1.5(m), 555+/−1.5 (s), 525+/−1.5 (m), 479+/−1.5 (m), 410+/−1.5 (m),401+/−1.5 (m), 307+/−1.5 (m)H1 form

XRD:

No. d[Å] 2θ l/lo 1 8.03 11.0 69 2 7.27 12.2 25 3 6.11 14.5 24 4 4.0122.1 86 5 3.64 24.5 100 6 3.26 27.3 51 7 3.08 29.0 29 8 3.04 29.4 34 92.82 31.7 61 10 2.66 33.6 26FT-IR bands (in cm⁻¹):3386+/−1.5 (m), 3080+/−3 (m), 1706+/−1.5 (s), 1691+/−1.5 (s), 1634+/−1.5(m), 1513+/−1.5 (m), 1445+/−1.5 (w), 1241+/−1.5 (w), 1079+/−1.5 (w),989+/−1.5 (w), 940+/−1.5 (w), 861+/−1.5 (w), 823+/−1.5 (w), 675+/−1.5(w), 603+/−1.5 (w), 573+/−1.5 (w), 549+/−1.5 (w), 527+/−1.5 (w)

For the purposes of this text, it is understood that the tautomericforms are included in the mention of a given group, for examplethio/mercapto or oxo/hydroxy.

The pharmaceutical compositions according to the present invention areuseful in the treatment of pathologies associated with insulinresistance syndrome (syndrome X).

Insulin resistance is characterised by a reduction in the action ofinsulin (cf. Presse Médicale, 1997, 26 (No. 14), 671-677) and isinvolved in a large number of pathological conditions, such as diabetesand more particularly non-insulin-dependent diabetes (type II diabetesor NIDDM), dyslipidaemia, obesity and arterial hypertension, and alsocertain microvascular and macrovascular complications, for instanceatherosclerosis, retinopathy and neuropathy.

In this respect, reference will be made, for example, to Diabetes, vol.37, 1988, 1595-1607; Journal of Diabetes and its Complications, 1998,12, 110-119 or Horm. Res., 1992, 38, 28-32.

The aim of the present invention is to propose a pharmaceuticalcomposition for significantly improving the condition of diabetics.

The pharmaceutical compositions of the invention especially havehypoglycaemiant activity.

The compounds of the formula (I) are therefore useful in the treatmentof pathologies associated with hyperglycaemia.

The pharmaceutical composition comprising the triazine compound of theformula (I) in combination with an insulin sensitiser can be prepared bymixing together the various active principles, either all together orindependently with a physiologically acceptable support, an excipient, abinder, a diluent, etc. It is then administered orally or non-orally,for instance via the parenteral, intravenous, cutaneous, nasal or rectalroute. If the active principles are formulated independently, thecorresponding formulations can be mixed together extemporaneously usinga diluent and are then administered or can be administered independentlyof each other, either successively or sequentially.

The pharmaceutical compositions of the invention include formulations,such as granules, powders, tablets, gel capsules, syrups, emulsions andsuspensions, and also forms used for non-oral administration, forinstance injections, sprays or suppositories.

The pharmaceutical forms can be prepared via the known conventionaltechniques.

The preparation of an orally administered solid pharmaceutical form willbe performed by the following process: an excipient (for examplelactose, sucrose, starch, mannitol, etc.), a disintegrant (for examplecalcium carbonate, calcium carboxymethylcellulose, alginic acid, sodiumcarboxymethylcellulose, colloidal silicon dioxide, sodiumcroscarmellose, Crospovidone, guar gum, magnesium aluminium silicate,microcrystalline cellulose, cellulose powder, pregelatinised starch,sodium alginate, starch glycolate, etc.), a binder (for examplealpha-starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose, alginic acid, carbomer, dextrin, ethylcellulose,sodium alginate, maltodextrin, liquid glucose, magnesium aluminiumsilicate, hydroxyethylcellulose, methylcellulose, guar gum, etc.) and alubricant (for example talc, magnesium stearate, polyethylene 6000,etc.) are, for example, added to to the active principle(s) and themixture obtained is then tabletted. If necessary, the tablet can becoated via the known techniques, in order to mask the taste (for examplewith cocoa powder, mint, borneol, cinnamon powder, etc.) or to allowenteric dissolution or sustained release of the active principles. Thecoating products that can be used are, for example, ethylcellulose,hydroxymethylcellulose, polyoxyethylene glycol, celluloseacetophthalate, hydroxypropylmethylcellulose phthalate and Eudragit®(methacrylic acid-acrylic acid copolymer), Opadry®(hydroxypropylmethylcellulose+macrogol+titanium oxide+lactosemonohydrate). Pharmaceutically acceptable colorants may be added (forexample yellow iron oxide, red iron oxide, quinoline yellow lake, etc.).Pharmaceutical forms, such as tablets, powders, sachets and gel capsulescan be used for an oral administration.

The liquid pharmaceutical forms for oral administration includesolutions, suspensions and emulsions. The aqueous solutions can beobtained by dissolving the active principles in water, followed byaddition of flavourings, colorants, stabilisers and thickener, ifnecessary. In order to improve the solubility, it is possible to addethanol, propylene glycol or other pharmaceutically acceptablenon-aqueous solvents. The aqueous suspensions for oral use can beobtained by dispersing the finely divided active principles in waterwith a viscous product, such as natural or synthetic gums, resins,methylcellulose or sodium carboxymethylcellulose.

The pharmaceutical forms for injection can be obtained, for example, bythe following process. The active principle(s) is (are) dissolved,suspended or emulsified either in an aqueous medium (for exampledistilled water, physiological saline, Ringer's solution, etc.) or in anoily medium (for example a plant oil, such as olive oil, sesameseed oil,cottonseed oil, corn oil, etc., or propylene glycol), with a dispersant(for example Tween 80, HCO 60 (Nikko Chemicals), polyethylene glycol,carboxymethylcellulose, sodium alginate, etc.), a preserving agent (forexample methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzylalcohol, chlorobutanol, phenol, etc.), an isotonicity agent (for examplesodium chloride, glycerol, sorbitol, glucose, etc.) and also otheradditives, such as, if desired, a solubilising agent (for example sodiumsalicylate, sodium acetate, etc.) or a stabiliser (for example humanserum albumin).

A pharmaceutical form for external use can be obtained from a solid,semi-solid or liquid composition containing the active principle(s). Forexample, to obtain a solid form, the active principle(s) is (are)treated, alone or as mixtures, with excipients (for example lactose,mannitol, starch, microcrystalline cellulose, sucrose, etc.) and athickener (for example natural gums, cellulose derivatives, acrylicpolymers, etc.) so as to convert them into powder. The liquidpharmaceutical compositions are prepared in substantially the same wayas the forms for injection, as indicated previously. The semi-solidpharmaceutical forms are preferably in the form of aqueous or oily gelsor in the form of a pomade. These compositions may optionally contain apH regulator (for example carbonic acid, phosphoric acid, citric acid,hydrochloric acid, sodium hydroxide, etc.) and a preserving agent (forexample p-hydroxybenzoic acid esters, chlorobutanol, benzalkoniumchloride, etc.) and also other additives.

The daily doses of the insulin sensitisers are between 0.5 mg and 50 mg.

More particularly, if, in the present invention, rosiglitazone is used,the daily dose is between 1 mg and 8 mg, more preferably 4 mg. Ifpioglitazone is used, the daily dose is between 15 mg and 45 mg. Ifmuraglitazar is used, the daily dose is between 0.5 mg and 20 mg,preferably 5 mg.

The daily doses of the compounds of the formula (I) are between 200 mgand 2000 mg.

The relative proportion of the constituents of the pharmaceuticalcompositions of the present invention takes into account the recommendeddosages of the respective active principles. These relative proportionsof insulin sensitisers, or of pharmaceutically acceptable salts thereof,and of the compounds of the formula (I), or of pharmaceuticallyacceptable salts thereof, thus vary in consequence. Preferably, theweight ratio of insulin sensitiser to the compound of the formula (I)ranges between 1/2 and 1/2000, more particularly from 1/4 to 1/2000 andespecially from 1/5 to 1/2000. The frequency of administration of thecompounds of the invention is between 1 and 2 administrations per day.In the case where the doses of compounds of the formula (I) necessitatemore than one daily administration, the amounts of insulin sensitisersand the insulin sensitiser/compound of the formula (I) ratios areadjusted in consequence.

The aim of the present invention is also to propose a method oftreatment to via co-administration of effective amounts of a compound ofthe formula (I) and of an insulin sensitiser, and also kits for allowingthis co-administration.

The present invention also relates to kits that are suitable for thetreatment by the methods described above. These kits comprise acomposition containing the compound of the formula (I) in the dosagesindicated above and a second composition containing the insulinsensitisers in the dosages indicated above, for a simultaneous, separateor sequential administration, in effective amounts according to theinvention.

The term “co-administration” means the simultaneous, separate orsequential administration of one or more compounds to the same patient,over a period that may be up to 2 hours or even up to 12 hours. Forexample, the term co-administration includes (1) a simultaneousadministration of the two compounds, (2) an administration of the first,followed 2 hours later by the administration of the second compound, (3)an administration of the first, followed 12 hours later by theadministration of the second compound.

The examples below of compositions according to the invention are givenas non-limiting illustrations.

EXAMPLES

The amounts are expressed on a weight basis.

Formulation Example 1

-   -   (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine        hydrochloride: 1000 mg    -   rosiglitazone: 4 mg    -   microcrystalline cellulose: 114 mg    -   croscarmellose: 28 mg    -   polyvinylpyrrolidone: 40 mg    -   magnesium stearate: 14 mg    -   Opadry: 24 mg

Formulation Example 2

-   -   (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine        hydrochloride: 1000 mg    -   pioglitazone: 25 mg    -   microcrystalline cellulose: 115.5 mg    -   croscarmellose: 28 mg    -   polyvinylpyrrolidone: 40 mg    -   magnesium stearate: 9 mg    -   Opadry®: 24 mg

Formulation Example 3

-   -   (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine        hydrochloride: 750 mg    -   rosiglitazone: 2 mg    -   microcrystalline cellulose: 110 mg    -   croscarmellose: 21 mg    -   polyvinylpyrrolidone: 30 mg    -   magnesium stearate: 10.5 mg    -   Opadry®: 18 mg

Formulation Example 4

-   -   (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine        hydrochloride: 1000 mg    -   muraglitazar: 5 mg    -   microcrystalline cellulose: 150 mg    -   croscarmellose: 24 mg    -   polyvinylpyrrolidone: 44 mg    -   magnesium stearate: 8 mg    -   Eudragit®: 24 mg

Biological Test: Modulation of Glucose Levels with the Combinations Ofthe Invention with Insulin Sensitisers

The capacity of the compounds of the invention in combination withinsulin-sensitising antidiabetic compounds to modify the blood glucoselevels is evaluated in vivo in diabetic GK rats.

Alone or in combination, the antidiabetic agents are administered twicea day (bid) to the GK rats for 4 days. The oral glucose tolerance test(OGTT) is performed after the last day of treatment.

OGTT is performed in the morning after 3 hours of fasting by oraladministration of a glucose charge of 2 g/kg of body mass. The bloodsamples are collected from the tail vein at 0; 10; 20; 30; 45; 60; 90and 120 minutes to determine the glucose levels.

Results for the Combinations According to the Invention

The combination of rosiglitazone and of the hydrochloride salt of(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine wastested as follows. The two compounds were administered alone and incombination. The doses used for the hydrochloride salt of(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine were 50and 100 mg/kg PO twice daily for 4 days. For rosiglitazone, the dosesused were 1 and 5 mg/kg PO twice daily for 4 days. The followingcombination was tested:

-   -   the hydrochloride salt of        (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine:        100 mg/kg and rosiglitazone: 5 mg/kg PO twice daily for 4 days.

Glycaemia Glycaemia after 4 days Glycaemia % de- before of R under thecrease in treatment treatment % variation curve AUC vs Treatment mmol/lmmol/l vs control (AUC) control Control GK n=8 12.93 +/− 0.41 13.10 +/−0.87 3343 + 262 (+)-2-amino-3,6-dihydro-4- 12.95 +/− 0.41 11.01 +/− 0.37  −16% 2688 +/− 99 −19.6% dimethylamino-6-methyl- 1,3,5-triazinehydrochloride salt 100 mg/kg bid Rosiglitazone 5 mg/kg bid 12.81 +/−0.27 10.52 +/− 0.84 −19.7% 2954 +/− 150 −11.6%(+)-2-amino-3,6-dihydro-4- 12.86 +/− 0.52 10.03 +/− 0.35 −23.4% 2311 +/−121 −30.9% dimethylamino-6-methyl- 1,3,5-triazine hydrochloride salt 100mg/kg bid + Rosiglitazone 5 mg/kg bid

After four days of treatment (placebo), the glycaemia of the control GKdiabetic rats was not modified or increased significantly. At doses of 5mg/kg of rosiglitazone and 100 mg/kg of the hydrochloride salt of(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, theseagents induced a decrease in the fasted plasmatic glucose level.However, better glucose tolerance was observed with the hydrochloridesalt of (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazinethan with rosiglitazone.

In combination, rosiglitazone 5 mg/kg and the hydrochloride salt of(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine 100mg/kg showed much better efficacy than each compound individually. Thecombination of an insulin sensitiser, such as rosiglitazone and of acompound, such as the hydrochloride salt of(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazinegenerates better activity on the glucose tolerance and the plasmaticglucose level of each than that of the compounds.

1. Pharmaceutical composition comprising, as active principle: i) aninsulin sensitiser, wherein the insulin sensitiser is a glitazone (TZD),and ii) a compound of the formula (I) in combination with one or morepharmaceutically acceptable excipients

in which: R1, R2, R3 and R4 are independently chosen from the followinggroups: H, (C1-C20)alkyl optionally substituted by (C1-C5)alkyl,(C2-C20)alkenyl, or (C6-C14)aryl(C1-C20)alkyl, or R1 and R2, on the onehand, and R3 and R4, on the other hand, possibly forming with thenitrogen atom an n-membered ring with n being between 3 and 8, R5 and R6are independently chosen from the following groups: H, (C1-C20)alkyloptionally substituted by hydroxyl, halogen, (C1-C5)alkyl ortrifluoromethyl, (C3-C8)cycloalkyl, (C6-C14)aryl optionally substitutedby hydroxyl or (C1-C5)alkoxy, (C1-C13)heteroaryl bearing one or moreheteroatoms chosen from N, O and S, or (C6-C14)aryl(C1-C5)alkyl, or R5and R6 possibly forming with the carbon atom to which they are attachedan m-membered ring with m being between 3 and 8, optionally containingone or more heteroatoms chosen from N, O and S and optionally beingsubstituted by hydroxyl, (C1-C5)alkyl, or (C6-C14)aryl(C1-C5)alkoxy, orR5 and R6 forming with the carbon atom a C10-C30 polycyclic residueoptionally substituted by hydroxyl, (C1-C5)alkyl, carboxyl,carboxymethyl or carboxyethyl, or a racemic form, tautomer, enantiomer,diastereoisomer, epimer or polymorph thereof, or a mixture thereof, or apharmaceutically acceptable salt thereof.
 2. The pharmaceuticalcomposition according to claim 1, comprising a compound of the formula(I) in which R5 is hydrogen.
 3. The pharmaceutical composition accordingto claim 1, comprising a compound of the formula (I) in which R5 and R6are independently chosen from H and (C1-C20)alkyl groups optionallysubstituted by hydroxyl, halogen, (C1-C5)alkyl, (C6-C14)aryloxy ortrifluoromethyl.
 4. The pharmaceutical composition according to claim 1,wherein R1, R2, R3 and R4 are independently chosen from H and(C1-C20)alkyl groups optionally substituted by (C1-C5)alkyl. 5.(canceled)
 6. The pharmaceutical composition according to claim 1,comprising a compound of the formula (I) in which R1 and R2 are a methylgroup and R3 and R4 represent a hydrogen.
 7. The pharmaceuticalcomposition according to claim 1, wherein the compound of formula (I) is2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, or apharmaceutically acceptable salt thereof.
 8. The pharmaceuticalcomposition according to claim 1, wherein the compound of formula (I) is(−)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, or apharmaceutically acceptable salt thereof.
 9. The pharmaceuticalcomposition according to claim 1, wherein the compound of formula (I) is(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, or apharmaceutically acceptable salt thereof.
 10. The pharmaceuticalcomposition according to claim 1, wherein the compound of the formula(I) is in the form of a hydrochloride salt. 11-12. (canceled)
 13. Thepharmaceutical composition according to claim 1, wherein the insulinsensitiser is selected from the group consisting of rosiglitazone andpioglitazone.
 14. (canceled)
 15. The pharmaceutical compositionaccording to claim 1, wherein the insulin sensitiser is in the form of apharmaceutically acceptable salt.
 16. The pharmaceutical compositionaccording to claim 1, wherein the composition contains between 0.5 mgand 50 mg of insulin sensitiser.
 17. The pharmaceutical compositionaccording to claim 1, wherein the composition contains between 200 mgand 2000 mg of compound of the formula (I).
 18. The pharmaceuticalcomposition according to claim 1, wherein the weight ratio of insulinsensitiser to the compound of the formula (I) is between 1/2 and 1/2000.19. The pharmaceutical composition according to claim 1, wherein theinsulin sensitiser is rosiglitazone and the compound of the formula (I)is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine, orits hydrochloride salt.
 20. The pharmaceutical composition according toclaim 1, wherein the insulin sensitiser is pioglitazone and the compoundof the formula (I) is(+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine or itshydrochloride salt. 21-22. (canceled)
 23. The pharmaceutical compositionaccording to claim 1, which is suitable for oral administration, inwhich the pharmaceutical composition is a powder, a coated tablet, a gelcapsule, a sachet, a solution, a suspension or an emulsion.
 24. A methodfor the treatment of diabetes comprising administering an insulinsensitiser, wherein the insulin sensitiser is a glitazone (TZD) incombination with a compound of the formula (I) according to claim
 1. 25.The method according to claim 24, for the treatment ofnon-insulin-dependent diabetes.
 26. A method for the treatment of atleast one of the pathologies associated with insulin resistancesyndrome, selected from the group consisting of dyslipidaemia, obesity,arterial hypertension, and microvascular and macrovascularcomplications, comprising administering an insulin sensitiser, whereinthe insulin sensitiser is a glitazone (TZD), in combination with acompound of formula (I) according to claim
 1. 27. The method accordingto claim 24, wherein the insulin sensitiser is selected from the groupconsisting of rosiglitazone and pioglitazone.
 28. (canceled)
 29. Themethod according to claim 24, wherein the administration of the compoundof formula (I) and that of the insulin sensitiser are simultaneous,separate or sequential.
 30. A kit comprising a compound of the formula(I) and an insulin sensitiser, for simultaneous, separate or sequentialadministration wherein the insulin sensitiser is a glitazone and formula(I) is as follows:

in which: R1, R2. R3 and R4 are independently chosen from the followinggroups: H, C1-C20)alkyl optionally substituted by (C1-C5)alkyl,(C2-C20)alkenyl, (C6-C14)aryl(C1-C20)alkyl, or R1 and R2, on the onehand, and R3 and R4, on the other hand, possibly forming with thenitrogen atom an n-membered ring with n being between 3 and 8, R5 and R6are independently chosen from the following groups: H, (C1-C20)alkyloptionally substituted by hydroxyl, halogen, (C1-C5)alkyl ortrifluoromethyl, (C3-C8)cycloalkyl, (C6-C14)aryl optionally substitutedby hydroxyl or (C1-C5)alkoxy, (C1-C13)heteroaryl bearing one or moreheteroatoms chosen from N, O and S or (C6-C14)aryl(C1-C5)alkyl, or R5and R6 possibly forming with the carbon atom to which they are attachedan m-membered ring with m being between 3 and 8, optionally containingone or more heteroatoms chosen from N, O and S and optionally beingsubstituted by hydroxyl, (C1-C5)alkyl, or (C6-C14)aryl(C1-C5)alkoxy, orR5 and R6 forming with the carbon atom a C10-C30 polycyclic residueoptionally substituted by hydroxyl, (C1-C5)alkyl, carboxyl,carboxymethyl or carboxyethyl, or a racemic form, tautomer, enantiomer,diastereoisomer, epimer or polymorph thereof or a mixture thereof, or apharmaceutically acceptable salt thereof.